A Phase I Study of Immune Checkpoint Inhibition (anti-CTLA4 and anti-PD-L1) in Combination with RadiationTherapy in Patients with Locally Advanced UnresectablePancreatic Cancer

Background: No clear consensus exists on the best treatment for unresectable locally advanced pancreatic cancer. Programmed death ligand-1 (PD-L1) inhibitors and cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitors, especially in combination, have been shown to increase survival in a variety of cancers. Preclinical data indicates potential synergy between immunotherapy, such as PD-L1 and CTLA-4 inhibitors, with radiation therapy. Specifically, in combination with Stereotactic Body Radiation Therapy (SBRT), immunotherapy may provide an effective treatment modality for this difficult-to-treat patient population. Aim: To determine the safety and recommended phase 2 dose (RP2D) of SBRT in combination with either (A) Durvalumab (MEDI4736) alone, (B) Tremelimumab alone or (C) the combination of Durvalumab (MEDI4736) and Tremelimumab for patients with unresectable locally advanced adenocarcinoma. Methods: A multi-institutional phase Ib trial of radiation therapy in combination with immune checkpoint inhibition (anti-CTLA4 alone, anti-PD-L1 alone, or anti-CTLA4 with anti-PDL1) in patients with unresectable locally advanced pancreatic cancer. Cohort A: SBRT plus Durvalumab (MEDI4736): 1 dose escalation Cohort B: SBRT plus Tremelimumab: 1 dose escalation Cohort C: SBRT plus Durvalumab (MEDI4736) in combination with Tremelimumab: For Durvalumab (MEDI4736), there will be either 1 dose escalation (if RP2D of Cohort A is >750mg) or no dose escalation (if RP2D of Cohort A is 750mg). For Tremelimumab, there will be flat dosing of 75 mg, no dose escalation. Each cohort will have a standard 3 + 3 dose escalation design. SBRT will be administered at the standard dose of 6.6 Gy daily for 5 days in each cohort.